.beta.-Cyclodextrin (.beta.-CD) is a cyclic oligosaccharide consisting of 7 glucose units which are joined by .alpha.-1,4 linkages: ##STR1##
It is obtained as a result of an enzymatic degradation of starch, during which a predominant amount of .beta.-CD is formed, apart from .alpha.-cyclodextrin (composed of 6 glucose units) and .gamma.-cyclodextrin (composed of 8 glucose units). As far as the chemical and physical-chemical properties of this class of compounds are concerned, reference is made to "Cyclodextrin-Einschlussverbindungen in Forschung und Industrie" (Cyclodextrin inclusion compounds in research and industry) [I] by W. Saenger, published in Angew. Chemie. 92, pp. 343 to 361 (1980), Verlag Chemi-Weinheim (DE) and to "Synthesis of Chemically Modified Cyclodextrins" [II] by A. P. Croft and R. A. Bartsch, published in Tetrahedron, Vol. 39, No. 9, pp. 1417 to 1474 (1983), Pergamon Press (GB). For the etherification reaction, a maximum of 3 OH groups are available per anhydro-D-glucose unit in the .beta.-cyclodextrin, i.e., the maximum number of OH groups per .beta.-cyclodextrin molecule is 21. Since known ethers of .beta.-cyclodextrin have primarily been synthesized as structurally well-defined compounds, they are generally ethers where one, two or the three OH groups of the carbon atoms 2, 3, and 6 of each anhydro-D-glucose salt unit are deliberately substituted; the degree of substitution (DS) of these compounds is then 1, 2 or 3. In principle, any intermediate degree is also possible, if the etherification proceeds in a statistical manner to give mixtures of compounds. Substitution of one OH group in the .beta.-cyclodextrin molecule results in an ether group (a DS of about 0.14). When there is such a low degree of etherification, some molecules are not etherified at all, whereas others are substituted at two or more OH groups. For practical purposes it is therefore reasonable to assume that at a DS of 0.3 of higher at least one OH group of each molecule is actually substituted.
The following ethers of .beta.-cyclodextrin are known from prior art:
In the first of the cited references [I] (p. 354), the methyl, sodium carboxymethyl and dihydroxypropyl ethers of .beta.-cyclodextrin are specifically mentioned; methods for their preparation are not described.
Apart from various methyl ethers of .beta.-cyclodextrin, the second of the cited publications [II] specifically mentions and describes the preparation of ethers which (at their carbon atoms 2 and 6) possess benzyl, allyl or vinyl groups and (at their carbon atoms 3) possess methyl groups; furthermore carboxymethyl and carboxyethyl ethers, cyanoethyl and sulfoethyl ethers are described (in particular on pages 1427 et seq.) The last-mentioned compounds are also described in U.S. Pat. No. 3,453,258 and in U.S. Pat. No. 3,426,011. The latter of these two patents provides a process variant (for the preparation of carboxymethyl ethers of .beta.-cyclodextrin) in which etherification is performed in the presence of an organic solvent (isopropanol) and an aqueous NaOH solution.
Hydroxyethyl and hydroxypropyl ethers and also a hydroxyethyl-hydroxypropyl mixed ether of .beta.-CD are referred to by U.S. Pat. No. 3,459,731.
In "Conformation of O-methylated Amylose and Cyclodextrins" [III], in Tetrahedron, Vol. 24, pp. 803 to 821 (1968), Pergamon Press, B. Casu et al. describe (a) methyl-.beta.-CD (DS about 2) which is disubstituted at the carbon atoms 2 and 6 and is obtained by reacting .beta.-CD with dimethyl sulfate in a dimethylformamide (DMF)/dimethyl sulfoxide (DMSO) mixture, in the presence of BaO, and (b) trisubstituted methyl-.beta.-CD (DS about 3), which is obtained by reacting .beta.-CD with methyl iodide in DMSO, in the presence of BaO.
In "Complex Formation between Mycobacterial Polysaccharides or Cyclodextrins and Palmitoyl Coenzyme A" [IV], published in The Journal of Biological Chemistry, Vol. 250, No. 4, pp. 1223 to 1230 (1975), R. Bergeron et al. describe (a) C-2 and C-6 disubstituted methyl .beta.-CD and propyl-.beta.-CD which are produced by reacting .beta.-CD with dimethyl sulfate or dipropyl sulfate, respectively, in a DMF/DMSO mixture, in the presence of BaO and Ba(OH).sub.2 ; (b) C-3 or C-6 monosubstituted methyl-.beta.-CD (DS about 1 or about 0.7), which are produced by reacting .beta.-CD provided with protective groups with methyl iodide or diazo methane; and (c) trisubstituted methyl-.beta.-CD which is produced by reacting disubstituted methyl-.beta.-CD with methyl iodide in a DMF/DMSO mixture in the presence of sodium hydride.
In "Properties of Cyclodextrins/Part III/Cyclodextrin-Epichlorohydrin Resins: Preparation and Analysis" [V], published in Die Starke (Starch), 21st year, No. 5, pp. 119 to 123 (1969), N. Wiedenhof et al. describe the preparation of .beta.-CD epichlorohydrin polymer beads and the corresponding water-soluble resins by reacting .beta.-CD with the bifunctionally reactive epichlorohydrin in methyl isobutyl ketone, in the presence of an aqueous 30% or 16% strength NaOH solution and NaBH.sub.4.
In "Properties of Cyclodextrins/Part VI/Water-Soluble Cyclodextrin-Derivatives, Preparation and Analysis" [VI], published in Die Starke, 23rd year, No. 5, pp. 167 to 171 (1971), J. Lammers et al. describe the preparation of (a) sodium carboxymethyl-.beta.-CD (DS about 0.45) by reacting .beta.-CD with monochloroacetic acid in a 30% strength aqueous NaOH solution, in the presence of NaBH.sub.4, and (b) sodium sulfopropyl-.beta.-CD (DS about 0.9) by reacting .beta.-CD with propanesultone in a 40% strength aqueous NaOH solution.
In "Synthesis of Heptakis (2-O-methyl-.beta.-cyclodextrin" [VII], published in Die Starke, 28th year, No. 7, pp. 226/227 (1976), K. Takeo et al. describe the preparation of methyl-.beta.-CD which is only substituted at the carbon atom 2 (DS about 1) and is obtained by methylating the C-6 brominated .beta.-CD with dimethylsulfate in DMF, in the presence of BaO and Ba(OH).sub.2 .times.8H.sub.2 O, and splitting off the bromine substituent.
In "Synthesis and .sup.13 C-NMR Spectroscopy of Methylated .beta.-Cyclodextrins" [VIII], published in "Starch/Starke", 32nd year, No. 5, pp. 165 to 169 (1980), J. Szejtli et al. describe the preparation of (a) the trisubstituted methyl-.beta.-CD by reacting .beta.-CD with methyl iodide in dry DMSO or DMF, in the presence of sodium hydride, and (b) C-2 and C-6 disubstituted methyl-.beta.-CD by reacting .beta.-CD with dimethyl sulfate in a mixture of DMSO and DMF, in the presence of BaO and Ba(OH).sub.2 .times.8H.sub.2 O.
JP-A No. 6883/79 describes liquid crystal elements which contain, for example, derivatives of .beta.-CD as a cyclic oligosaccharide, whereby, in accordance with the general formula indicated in that publication, a great number of different hydroxyalkyl ethers or aminoalkyl ethers are said to be possible. The only derivative of .beta.-CD specifically mentioned in the specification is hydroxypropyl-.beta.-CD. DE-A No. 27 04 776 relates to similar subject matter, but in that patent publication, too, only hydroxypropyl-.beta.-CD is specifically mentioned.
WO-A No. 83/00809 refers to the use of swellable .beta.-cyclodextrin derivatives in tablets, whereby the derivatives are obtained from .beta.-CD by reacting it with bifunctionally-reactive compounds, such as epichlorohydrin, in an aqueous-alkaline medium. The preparation of this type of derivative is also known from DE-B No. 14 93 047 or, with the addition of cellulose, from DE-A No. 31 30 502.
The water-soluble inclusion complexes according to DE-A No. 31 18 218 are formed from methyl-.beta.-CD and biologically-active organic compounds (for example, vitamins or steroid hormones) and are said to contain a "partially methylated .beta.-cyclodextrin", i.e., a molecule in which at least one and not more than 20 hydroxyl groups are etherified (DS about 0.14 to about 2.86). The methyl-.beta.-CD types are said to consist either of homogeneous molecules or of mixtures of molecules of different degrees of substitution, preference being given to a methyl-.beta.-CD which (on an average) is disubstituted, i.e., has a DS of about 2. As far as the preparation of the derivatives is concerned, the publication refers to the previously-mentioned references.
In the recent past .beta.-cyclodextrin has gained more and more in importance because processes have apparently been developed which permit cost-advantageous production on a large industrial scale.